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Transgenic Res. 2015 Dec;24(6):1029-42. doi: 10.1007/s11248-015-9912-6. Epub 2015 Oct 28.

Transgenic Wuzhishan minipigs designed to express a dominant-negative porcine growth hormone receptor display small stature and a perturbed insulin/IGF-1 pathway.

Li F1,2, Li Y1,3,2, Liu H1,2, Zhang X1,2, Liu C1,2, Tian K1,2, Bolund L1,4, Dou H3,2, Yang W3,2, Yang H1, Staunstrup NH5, Du Y6,7,8.

Author information

1
BGI-Shenzhen, Shenzhen, 518083, China.
2
ShenZhen Engineering Laboratory for Genomics-Assisted Animal Breeding, BGI-Shenzhen, 8F Main Building, Beishan Industrial Zone, Yantian District, Shenzhen, 518083, China.
3
BGI Ark Biotechnology (BAB), Shenzhen, 518083, China.
4
Department of Biomedicine, Aarhus University, Wilhelm Meyers allé 1240, 8000, Aarhus C, Denmark.
5
Department of Biomedicine, Aarhus University, Wilhelm Meyers allé 1240, 8000, Aarhus C, Denmark. nhs@clin.au.dk.
6
BGI-Shenzhen, Shenzhen, 518083, China. duyt@genomics.cn.
7
BGI Ark Biotechnology (BAB), Shenzhen, 518083, China. duyt@genomics.cn.
8
ShenZhen Engineering Laboratory for Genomics-Assisted Animal Breeding, BGI-Shenzhen, 8F Main Building, Beishan Industrial Zone, Yantian District, Shenzhen, 518083, China. duyt@genomics.cn.

Abstract

Growth hormone (GH) is an anabolic mitogen with widespread influence on cellular growth and differentiation as well as on glucose and lipid metabolism. GH binding to the growth hormone receptor (GHR) on hepatocytes prompts expression of insulin growth factor I (IGF-1) involved in nutritionally induced compensatory hyperplasia of pancreatic β-cell islets and insulin release. A prolonged hyperactivity of the IGF-1/insulin axis in the face of insulinotropic nutrition, on the other hand, can lead to collapse of the pancreatic islets and glucose intolerance. Individuals with Laron syndrome carry mutations in the GHR gene resulting in severe congenital IGF-1 deficiency and elevated GH serum levels leading to short stature as well as perturbed lipid and glucose metabolism. However, these individuals enjoy a reduced prevalence of acne, cancer and possibly diabetes. Minipigs have become important biomedical models for human conditions due to similarities in organ anatomy, physiology, and metabolism relative to humans. The purpose of this study was to generate transgenic Wuzhishan minipigs by handmade cloning with impaired systemic GHR activity and assess their growth profile and glucose metabolism. Transgenic minipigs featuring overexpression of a dominant-negative porcine GHR (GHR(dm)) presented postnatal growth retardation and proportionate dwarfism. Molecular changes included elevated GH serum levels and mild hyperglycemia. We believe that this model may prove valuable in the study of GH functions in relation to cancer, diabetes and longevity.

KEYWORDS:

Growth hormone; Laron syndrome; Metabolic syndrome; Pig cloning

PMID:
26510874
DOI:
10.1007/s11248-015-9912-6
[Indexed for MEDLINE]

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